Lung infections represent the greatest disease burden worldwide and a leading cause of mortality, the latter of which is virtually unimproved since the discovery of antibiotics many decades ago. Pneumonia is also the most common cause of sepsis, which itself is a major public health concern and the leading cause of mortality in hospitalized patients. A better understanding of protective pathways initiated during pneumonia to counter bacteremia and organ injury, both of which are characteristic of sepsis, is necessary given the threat of pneumonia-induced sepsis. The hepatic acute phase response, a hallmark of infection and inflammation, involves the synthesis of myriad APPs and other liver-specific processes, and is generally believed to benefit the host. But whether and how it does so remains unclear. We have previously shown that the hepatocyte transcription factors STAT3 and NF-kB RelA are together necessary for establishing the liver acute phase response during pneumonia. Moreover, our recent pilot studies suggest that the absence of RelA alone promotes mortality, liver injury and bacteremia, possibly due to dysregulation of hepatic leukocyte function and increased programmed cell death. Liver injury is a common and important feature of sepsis, and these preliminary results implicate hepatocyte RelA-dependent gene programs as a gatekeeper to compartmentalize lung infections and limit the incidence of damaging systemic sequelae. Given these findings, we will test the central hypothesis that RelA-dependent gene programs counter damaging signals from hepatic leukocytes to maintain liver homeostasis and limit the systemic consequences of pneumonia. In Specific Aim 1, we will conclusively determine the influence of hepatocyte RelA on liver injury and systemic host defense during pneumonia, and we will utilize cell sorting and pharmacological loss-of-function approaches to examine the influence of NKT and Kupffer cells on liver injury during pneumonia. In Specific Aim 2, we will determine whether programmed cell death initiated by death receptor signaling (extrinsic apoptosis and/or necroptosis) is mechanistically linked to pneumonia-induced hepatotoxicity. Furthermore, studies proposed in this aim will begin to investigate whether DAMPs are released from dying hepatocytes and may promote a viscous cycle whereby increased immunotoxicity perpetuates liver injury downstream of pneumonia. These studies will be complemented by liver transcriptional profiling to provide and unbiased and comprehensive assessment of candidate molecular networks through which the liver preserves systemic homeostasis in response to lung infection. We anticipate that these investigations will shed new light on pathways controlling the severity and/or incidence of pneumonia-induced sepsis, possibly providing a basis for future clinical interventions within this patient population.